The present invention relates generally to methods for performing microbeam therapy on a subject for treatment of tumors, neurological targets and of other diseases, and more particularly to methods of delivering therapeutic microbeam arrays of protons and heavy ions to produce a broad beam, i.e., solid beam effect only within a target volume thus increasing the therapeutic effect of the microbeam radiation therapy method.
Cancer continues to be one of the foremost health problems. Conventional treatments such as surgery, chemotherapy and radiation therapy have exhibited favorable results in many cases, while failing to be completely satisfactory and effective in all instances. For example, conventional radiation therapy has serious limitations due to radiation damage to normal tissues. Although stereotactic radiosurgery has improved the outcomes, highly radiosensitive structures located in the vicinity of the target remain a limiting factor. It is well known to those skilled in the art that the threshold dose, or maximum tolerable dose before neurological and other complications of radiotherapy arise, increases as irradiated volumes of tissue are made smaller. Such observations eventually led to the development of grid radiotherapy using grids or sieves for spatial fractionation of the X-ray exposure field at the body's surface, and also to the development of stereotactic radiosurgery.
Recently, an alternative form of radiation therapy, known as microbeam radiation therapy (MRT), has been investigated in laboratory animals to treat tumors such as those for which the conventional methods have limited effectiveness or are associated with a high risk factor. The concept of MRT was introduced in U.S. Pat. No. 5,339,347 to Slatkin et al. MRT differs from conventional radiation therapy by employing arrays of parallel planes of x-rays, which are at least one order of magnitude smaller in thickness (or diameter if parallel cylindrical beams are used rather than planar beams) than the smallest radiation beams in current conventional clinical use. These very thin microbeams, which are also called microplanar beams, can be generated using the high intensity x-ray beams that are currently generated only at synchrotron electron storage rings.
The tissue-sparing effect of microbeams for beam thicknesses between 0.02 mm and 0.7 mm has been established in a large variety of tissue types, including the brain and spinal cord in very young and adult laboratory animals. This tissue-sparing phenomenon has been attributed to two separate effects. According to the first effect, called the “dose-volume tissue-repair effect,” tissues can tolerate larger doses when the irradiated volume is made smaller. According to the second effect, called “microscopic prompt tissue repair effect,” when the beam thickness is a small fraction of a millimeter, several biological tissue repair mechanisms become effective promptly, i.e., within hours or days, and repair the damage to the tissue.
In a new development in MRT, two arrays of planar x-ray microbeams aimed at the target from 90-degreee angles were “interlaced” (or “interleaved”) with each other to produce an unsegmented radiation field at the target. This concept is the subject of U.S. Pat. Nos. 7,158,607 and 7,194,063 to Dilmanian, the specifications of which are incorporated herein by reference. In order to obtain an unsegmented, i.e., solid radiation field at the target, the gaps between the microbeams are made equal or slightly smaller than the thickness of each microbeams, and one array is shifted with respect to the other in the direction perpendicular to the planes of the microbeams by half the value of the beam spacing on-center. Therefore, the target receives an unsegmented radiation field (i.e., broad or solid beam), which can be lethal at a single fraction of 30-90 Gy, while the normal tissues surrounding the target receive only segmented beams, which spare normal tissues at those doses.
There are four advantages interlaced x-ray microbeams have over the conventional, unsegmented beams (called broad beams) currently used in clinical radiation therapy. First, interlaced microbeams spare the normal tissues surrounding the tumor because they are exposed to single arrays of microbeams only, which is tissue sparing. Second, because the microbeams are produced by synchrotron sources, which produce highly parallel beams, and because their beam energy is much smaller than those used in conventional radiation therapy, the dose falls very sharply at the edge of the target volume. This allows the treatment of very small tumors or neurological targets without unnecessarily exposing much of the surrounding normal tissues. Third, the radiation is administered in a single exposure (called single dose-fraction) instead of up to 40 daily dose fractions used in conventional radiation therapy. Finally, in the treatment of the tumors in the brain and the spinal cord, because of the sparing effect of the microbeams in the surrounding normal tissues, the treatment can be repeated if the tumor re-grows or if later another tumor develops in the brain or in the vicinity of the first tumor in the spinal cord.
The interlaced microbeam radiation methods disclosed in the '607 and '063 Dilmanian patents use arrays of parallel planar beams, each 0.3 to 0.7 mm in thickness in which the beam spacing on-center is twice the beam thickness (and therefore the gaps between the beams is equal to the beam thickness). In this method the target is aimed with two such arrays from orthogonal angles in a configuration in which the microplanar beams in the two arrays are parallel to each other. One array is shifted with respect to the other in the direction of the vector perpendicular to the microplanar beams by a distance equal to the gap between the beams. As a result, the two arrays interlace at the target, producing a non-segmented radiation field at the target.
However, a problem with x-ray microbeam delivery systems involves an important concept known as the “valley dose.” The term “valley dose” refers to the radiation leakage between microbeams of x-rays caused mostly by x-ray scattering. This leakage or scattering of x-rays between the delivered beams can damage normal tissue not being targeted, or jeopardize the otherwise robust biological repair processes involved with microbeam irradiations of normal tissues. For the normal tissues surrounding the target to be spared from the radiation, the valley dose in the normal tissue should be adequately low to allow the supportive cells in charge of tissue repair to survive.
Protons and heavy ions, mostly carbon, are also being used in clinical radiation therapy with some success. They have two main advantages over x-rays in their implementation for radiation therapy. First, because of their Bragg-peak feature of dose distribution in tissues in which the dose is mostly deposited in the last few millimeters of the particles' trajectory, and consequently because of their lack of target exit dose, they produce tighter dose distributions around the target volume than x-rays. Second, heavy charged particles particularly heavy ions such as carbons have a much larger Radiobiological Effectiveness (RBE) than x-rays, a factor that is particularly important in treating hypoxic and other radio resistant tumors. In particular, the RBE of heavy ions can be as large as 4.0, while that of protons is commonly less than 1.3.
Although the results from proton therapy are generally better than those from the present x-ray and gamma-ray (as in gamma-knife) methods, the difference is modest except probably for treating pediatric brain tumors. Furthermore, conventional heavy ion therapy has limitations because of its potential to damage normal tissues around the target at the therapeutic doses.
While protons have some advantages over x-rays, there has heretofore been no attempt to implement proton therapy with microbeams because their beams widen excessively as they pass through the tissue, an effect called “angular straggling.” For example, the width of a 1 mm proton beam can increase to about 2.5 mm when passing through 12 cm of tissue. However, the angular straggling effect of heavy ions is much smaller than that for protons because of the higher linear momentum of the heavy ions for the penetration to same tissue depth.
Accordingly, it would be desirable to combine the technologies of microbeam radiation therapy with heavy ion therapy to address some of the difficulties encountered in today's radiation therapy and radiosurgery. In particular, there is a need in the medical field for effective implementation of heavy ion therapy utilizing modern microbeam technologies. Further, there is a need for efficient devices for implementing interlaced heavy ion microbeams, which greatly enhance the possibility of delivery of therapeutic dose at a target while maintaining a safe dose to normal tissue.